The Id proteins are negative regulators of helix-loop-helix mediated gene expression and have been shown to play a key role in facilitating tumor angipgenesis in murine model systems. The role of Id in the epithelial compartment of various tumors however is controversial. Experiments described in this proposal tackle head on the question of whether the Id proteins are expressed in the epithelial compartment of any mouse or human breast cancer and if this expression is necessary or sufficient for tumor initiation or progression. Since it is likely that the discrepancy in the Id1 expression data in breast cancers is due to variability in the specificity of antibodies obtained from commercial sources, we developed a rabbit monoclonal antibody against purified murine Id1 with exquisite specificity and high avidity. Our results demonstrate that Id1 protein is present in the MMTV-wnt1 mouse model of breast cancer and in tumor cells derived from a restricted subset of human mammary tumors known as metaplastic carcinomas, usually associated with a poor prognosis. Experiments described below are aimed at determining if Id1 expression (alone or in combination with the observed Id3 expression) plays a role in the development and metastatic spread of these tumors. Preliminary data suggest that disruption of both Id1 and Id3 is required for significant effects on the tumor biology. The development of methods to inhibit the levels of these proteins in living animals is further described as part of the current proposal. Ultimately we will be able to explore the possibility that targeted therapies against the Id proteins both in the vasculature and the epithelial compartment of certain tumors will provide a valuable combination therapy for the management of human disease.